CN107405302A - 用于在耳道中局部施用的组合物 - Google Patents
用于在耳道中局部施用的组合物 Download PDFInfo
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- CN107405302A CN107405302A CN201680007801.8A CN201680007801A CN107405302A CN 107405302 A CN107405302 A CN 107405302A CN 201680007801 A CN201680007801 A CN 201680007801A CN 107405302 A CN107405302 A CN 107405302A
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Classifications
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Landscapes
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- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
Abstract
用于在耳道中局部施用的组合物的用途，包括：占组合物总重量的5％至40％的具有式R‑COOH的羧酸的维生素E的酯，其中R是具有1至19个碳原子的烷基或具有2至19个碳原子的烯基或炔基；以及油性赋形剂，其选自氢化聚异丁烯、氢化聚癸烯、氢化聚异丁烯和/或氢化聚癸烯与氢化聚烯烃的混合物，特别是氢化6至14个碳的氢化聚烯烃、辛酸/癸酸甘油三酯、环戊硅氧烷、及其混合物；该组合物用于从耳道中除去耳垢，以及用于在当个人佩戴助听器或使用耳塞保护听力而有摩擦应力的情况下，使耳道上皮细胞恢复正常。
Description
技术领域
本发明涉及制药工业领域。本发明尤其涉及一种用于在耳道中局部施用的组合物，特别是用于从耳道中除去耳垢，以及在例如当个人佩戴助听器或使用耳塞保护听力而有摩擦应力的情况下使耳道的上皮细胞恢复正常。
背景技术
在耳道中形成的耳垢是由皮脂腺产生的皮脂和轻度改性的汗腺(slightlymodified sweat gland，称为“耵聍腺”)的分泌物。耳垢连同皮脂和汗腺的分泌物含有大量从覆盖外耳道的上皮细胞的角质层剥离的角质细胞。
如在此所用的“耳道”是指外耳道(outer auditory canal)或外耳道(outerauditory meatus)。
保留在耳道中而未被排出的过量耳垢可能导致耵聍栓塞(earwax plug)的形成。
因此，由于耳垢分泌物在外耳道中的积累，耵聍栓塞是耳部堵塞。由于卫生或病理性原因，当耳垢不能流到耳廓外时，形成“栓塞(plug)”。在生理条件下，确实，存在于耳道中的细毛(thin hair)有助于将耳垢从内向外流出，从而防止耳垢物质停留在耳道中。
当产生的耳垢分泌物的量太多时，或当其正常的外流动作改变时，形成耵聍栓塞。这可以是多种原因导致的，例如脂溢性皮炎、牛皮癣、衰老(老年人的耵聍腺营养不良，因此产生干燥的耳垢更难以被向外滑动)、耳内过量的水使得耳垢肿胀、耳炎、助听器防止耳垢生理上流出、用棉签进行不适当的耳部护理。
为了去除耵聍栓塞，使用油性或水溶液，但其缺乏临床效果。
在帮助清除耵聍栓塞的商业产品中，(由二甲苯和杏仁油溶液组成)目前是最常用的。
根据本发明人的临床经验，在日间医院接受耵聍栓塞除去的那些患者的耳镜检查，他们在前些天在家里已经使用滴剂后，-根据需要通过冲洗或抽吸清除耵聍栓塞后-显示覆盖耳道的皮肤的严重形态学变化，其具有红化、去上皮化(de-epithelialization)，直到与疼痛症状和烧灼感相关的连续破坏性的损伤(在基于从堵塞形成到其去除的时间的可变百分比中，约30％的患者可计算，主要是针对对问题感知较少的儿科患者和老年患者)。
专利申请WO2011/85155描述了通过在外耳道中以滴剂、泡沫或凝胶形式滴注或喷雾来施用基于柠檬烯或胆汁盐或碳酸氢钠或其混合物去除耳垢的制剂。
专利申请WO2013/65051描述了一种喷雾颗粒形式的药物组合物，其包含橄榄角鲨烷和油性赋形剂，其可由矿物油或植物油组成，特别是由轻质矿物油和杏仁油组成。该组合物还可以包括精油(essential oil)、保湿油(moisturizing oil)和/或消毒剂油(disinfectant oil)，并且其经受至少5巴的压力，以给予颗粒足够的动能以将至少部分固体耳垢转化成流体状态的耳垢。
在Yahav Oron等人的文章中(“Cerumen removal：Comparison of cerumenolyticagents and effect on cognition in the elderly”，33-36，ARCHIVES OF GERONTOLOGYAND GERIATRICS，38，39Elsevier，Amsterdam，vol.52，n.2，2010年4月24日，第228-232页)，比较了三种用于去除耳垢的产品：
-由矿物油、角鲨烷和水薄荷(water mint)组成；
-由过氧化脲和无水甘油组成；
-由花生油、氯丁醇和二氯苯组成。
在同一篇文章中，提到的已被用于除去耳垢几种物质，如水、橄榄油、过氧化氢、乙酸和碳酸氢钠。
意大利专利号为IT1375669的专利文献描述了一种用于从耳道中除去耳垢的组合物，其包含40重量％至98重量％的在室温下为流体的脂质混合物以及2重量％至40重量％的至少一种非离子的、阴离子的、两性的或阳离子的乳化物质。该组合物可以进一步包含0.005重量％至3.0重量％的抗氧化剂，其可以是例如：生育酚或生育酚乙酸酯。该发明提供一种组合物的实施例(实施例1)，以重量百分比计，其包含16％的乙基己酸乙基己酯、30％的辛基十二烷醇、20％的C12-C15烷基苯甲酸酯、20％的棕榈酸乙基己酯、12.5％的聚山梨醇酯85、1％的生育酚乙酸酯和0.5％的抗菌剂。
“生物油”产品，在网站https://www.bio-oil.com/en/product/ingredients,上描述，包括许多成分，其中有几种精油和维生素，包括生育酚乙酸酯和油性赋形剂。使用该产品的适应症包括在疤痕、妊娠纹、肤色不均、皮肤老化和脱水皮肤的情况下的施用。没有与在耳道中可能的局部施用有关的报道。
发明内容
本发明的目的是提供一种用于在耳道中局部施用的组合物。
该目的是通过用于在耳道中局部施用的组合物的非治疗性用途来实现的，该组合物包括：占组合物总重量的5％至40％的具有式R-COOH的羧酸的维生素E的酯，其中R是具有1至19个碳原子的烷基或具有2至19个碳原子的烯基或炔基；以及油性赋形剂(oilyvehicle)，其选自氢化聚异丁烯(hydrogenated polyisobutene)、氢化聚癸烯(hydrogenated polydecene)、氢化聚异丁烯和/或氢化聚癸烯与氢化聚烯烃的混合物，特别是氢化6至14个碳的氢化聚烯烃、辛酸/癸酸甘油三酯(Caprylic/CapricTriglyceride)、环戊硅氧烷(Cyclopentasiloxane)、及其混合物。
根据本发明的一个方面，该组合物旨在用于清洁耳道。
根据本发明的另一方面，该组合物用于从耳道除去耳垢。
根据本发明的另一方面，该组合物旨在用于在当个人佩戴助听器或使用耳塞保护听力而有摩擦应力的情况下，使耳道上皮细胞恢复正常。
优选地，除了所述维生素E的酯和所述油性赋形剂之外，上述组合物不包含任何其它成分。
维生素E是指：d-α-生育酚、α-生育酚的d和l两种对映异构体的混合物、其他生育酚(β，γ，δ，ε，ζ，η)的混合物或生育三烯酚(tocotrienols)。
优选地，上述酯是维生素E乙酸酯、正丙酸酯或亚油酸酯。
特别优选的是使用维生素E乙酸酯，尤其是α-生育酚乙酸酯。
优选地，所述组合物包括占组合物总重量10％至30％的所述维生素E的酯。
特别优选的油性赋形剂由氢化聚癸烯(hydrogenated polydecene)和辛酸/癸酸甘油三酯(Caprylic/Capric Triglyceride)组成。
特别优选的组合物由α-生育酚乙酸酯和氢化聚癸烯组成。
有利地，该组合物由10-30％的α-生育酚乙酸酯和70-90％的氢化聚癸烯组成。
另一特别优选的组合物由α-生育酚乙酸酯和辛酸/癸酸甘油三酯(Caprylic/Capric Triglyceride)组成。
有利地，该组合物由10-30％的α-生育酚乙酸酯和70-90％的辛酸/癸酸甘油三酯(Caprylic/Capric Triglyceride)组成。
由于其与皮肤脂质的亲和力，本发明中使用的组合物有助于使耳垢流态化并溶解，从而在不使用棉签的情况下使耳垢自然从耳道流出，并且适合于防止并去除耵聍栓塞。根据本发明的组合物对于那些使用助听器的个人和长期使用耳机的个人特别有用。
除非另有说明，在本申请中给出的所有百分比都应理解为占组合物总重量的重量百分比。
具体实施方式
申请人已经生产多年基于α-生育酚乙酸酯的喷雾形式的制剂，以名称(14％α-生育酚乙酸酯和86％氢化聚癸烯)出售，用于口咽腔的粘膜(oral-pharyngeal mucosa)，具有润肤和保护作用。申请人还以油、亲脂性凝胶、喷雾剂和霜剂的形式制备用于皮肤保湿以及用于辅助治疗皮肤病的制剂。考虑到在将上述制剂施用于皮肤和粘膜期间观察到的有益效果，并且考虑到制剂以喷雾形式易于施用，申请人考虑验证后者的一种产品是否显示出对耳道上皮细胞有良好的疗效。
如以下所述的试验结果所示，实际上观察到，产品使耳道的上皮细胞恢复正常，特别适用于除去耳垢。
临床试验1
在2013年9月至2014年6月期间招募了年龄介于16至72岁(平均年龄55岁)之间的患者(11名女性和19名男性)30名，显示由于耳道中存在耳垢塞而导致闭塞感和传导性耳聋。
所用治疗方案用于根据以下剂量在耳道中局部施用喷雾：在除去耵聍栓塞之前，5天内喷洒3次/天。
与以前在家中使用或其他指定用于除去耵聍栓塞的商业耳部滴剂(例如)进行治疗的患者的情况相比，在所有接受上述治疗的患者中，耵聍栓塞除去的结果更容易。在耳内灌注后进行耳镜检查时，在所有使用的患者中观察到，耳道上皮细胞的颜色和营养性呈现绝对正常外观，没有发红、脱皮或擦伤的现象，而那些使用的患者在灌注前5天内，呈现出至少发红的现象并且在若干案例中还出现脱皮和擦伤现象。
因此，在除去前的5天内将施用于耳道的效果是令人吃惊的，因为其允许通过耳朵灌注去除耵聍栓塞，显着减少抽取时间，同时允许保证正常的上皮细胞营养作用，而不会发生任何一种副作用(发红、烧灼感、甚至严重的去上皮化)，而这些副作用是在使用不同于的其他商业耳部用品的个体中进行的灌注后非常普遍发生的。
上述患者中出现过复发性耵聍栓塞的20位患者，在除去栓塞的耳朵灌注后，建议使用喷雾每周3次，每次至少30分钟，在洗澡前施用6个月。在随访期间的所有个体中，没有观察到新的耵聍栓塞形成，并观察到耳道上皮细胞的营养正常的外观，没有发红或脱皮。产品耐受性为100％，在重复和连续施用后，没有个体显示副作用。
临床试验2
30名具有耳道慢性湿疹患者已受邀在每天晚上施用一次喷雾一次，持续1个月。在30天后的随访期间，在耳镜检查中，观察到70％的病例中的耳道上皮细胞外观完全正常，而在余下的30％的病例中，发现发红和上皮脱落显着减少。在所有的病例中，患者报告早在伴有个人主观缓解的的第二次施用以来，出现瘙痒和烧灼感减少，直到其消失。
临床试验3
15名佩戴助听器的个人，抱怨瘙痒和烧灼症状，以及由使用助听器产生的摩擦应力和连续每日摩擦所导致的听觉沉重现象，要求他们拿掉助听器后每天晚上施用一次喷雾，持续1个月。
在的第二次施用后，所有涉及的个人均报告了对助听器的更好的耐受性，上述现象显着减少，并且在使用的整个期间内持续受益。
这些结果表明，的施用也可以帮助所有使用耳塞作为听力保护的工作条件的人们。
还制备以下制剂：
(1)
α-生育酚亚油酸酯 14％
氢化聚癸烯 86％
(2)
α-生育酚乙酸酯 10％
氢化聚异丁烯 90％
(3)
α-生育酚乙酸酯 14％
辛酸/癸酸甘油三酯(Caprylic/Capric Triglyceride) 86％
在上述临床试验1的相同试验条件下，对5名患者的三个相应组施用上述三组制剂进行的初步试验，显示了由于耳道中耵聍栓塞的存在而导致的闭塞和传导性耳聋的感知，给出了与用产品的试验中获得的结果相当。
在上述临床试验2的相同试验条件下，上述三种制剂也分别对三个相应组的5名具有耳道慢性湿疹的患者进行了测试，所有患者均进行所获得的结果与使用的试验中获得的结果相当。
在与临床试验2相同的实验条件下，在具有耳道慢性湿疹的五名患者的三个组中也测试了上述三种制剂，所获得的结果与使用的试验中获得的结果相当。
此外，对本发明中使用的组合物与根据专利文献IT1375669的实施例1的组合物两者的耵聍溶解活性进行了比较试验。
比较以下制剂：
(1)氢化聚癸烯86g和生育酚乙酸酯14g；
(2)乙基己酸乙基己酯16g，辛基十二烷醇30g，C12-C15烷基苯甲酸酯20g，棕榈酸乙基己酯20g，生育酚乙酸酯1g，聚山梨醇酯85 12.5g，苯氧乙醇(抗菌剂)0.5g；
(3)辛酸/癸酸甘油三酯86g，生育酚乙酸酯14g。
由在医生办公室专门从事耳鼻咽喉科的医生进行机械去除收集到25个耳垢样品。
将由此获得的样品一起研磨以获得均匀的混合物。
将上述三种制剂分别加入到三个相应的试管中，其中每个试管分别含有110(±1.5)mg先前研磨的耳垢，如下所示：
试管1：1.0g制剂1+0.1125g耳垢；
试管2：1.0g制剂2+0.1142g耳垢；
试管3：1.0g制剂3+0.1146g的耳垢。
在制备后将三个试管平缓振荡18小时，制备后5天，从试管中提取出仍未溶解的耳垢。将经提取的耳垢样品保持干燥至恒重。
所得结果总结在下表中。
从上表可以看出，5天后可以推出：
-制剂1(包含在试管1中，由氢化聚癸烯86g+生育酚乙酸酯14g组成)溶解0.0168g耳垢，即总耳垢的14.93％；
-制剂2(包含在试管2号中，根据专利文献IT1375669的实施例1)溶解0.0066g耳垢，即总耳垢的5.78％；
-制剂3(包含在试管3中，由辛酸/癸酸甘油三酯86g+生育酚乙酸酯14g组成)溶解0.0130g耳垢，即总耳垢的11.34％。
从上述比较例可清楚地看到，本发明所使用的组合物发挥了明显高于(基本上为双倍)专利文献IT1375669的已知的制剂的耵聍溶解活性。
Claims (14)
1.用于在耳道中局部施用的组合物的非治疗性用途，包括：占组合物总重量的5％至40％的具有式R-COOH的羧酸的维生素E的酯，其中R是具有1至19个碳原子的烷基或具有2至19个碳原子的烯基或炔基；以及油性赋形剂，其选自氢化聚异丁烯、氢化聚癸烯、氢化聚异丁烯和/或氢化聚癸烯与氢化聚烯烃的混合物，特别是氢化6至14个碳的氢化聚烯烃、辛酸/癸酸甘油三酯、环戊硅氧烷、及其混合物。
2.根据权利要求1所述的用途，用于耳道的清洁。
3.根据权利要求1所述的用途，用于从耳道中除去耳垢。
4.根据权利要求1所述的用途，用于在当个人佩戴助听器或使用耳塞保护听力而有摩擦应力的情况下，使耳道上皮细胞恢复正常。
5.根据权利要求1至4中的任一项所述的用途，其中，所述维生素E的酯是维生素E乙酸酯、正丙酸酯或亚油酸酯，优选为α-生育酚乙酸酯。
6.根据权利要求1至5中的任一项所述的用途，其中，所述组合物包括占组合物总重量10％至30％的所述维生素E的酯。
7.根据权利要求1至6中的任一项所述的用途，其中，所述油性赋形剂由氢化聚癸烯组成。
8.根据权利要求7所述的用途，其中，所述维生素E的酯是α-生育酚乙酸酯。
9.根据权利要求8所述的用途，其中，所述组合物由α-生育酚乙酸酯和氢化聚癸烯组成。
10.根据权利要求9所述的用途，其中，所述组合物由10-30％的α-生育酚乙酸酯和70-90％的氢化聚癸烯组成。
11.根据权利要求1至6中的任一项所述的用途，其中，所油性述赋形剂由辛酸/癸酸甘油三酯(Caprylic/Capric Triglyceride)组成。
12.根据权利要求11所述的用途，其中，所述维生素E的酯是α-生育酚乙酸酯。
13.根据权利要求12所述的用途，其中，所述组合物由α-生育酚乙酸酯和辛酸/癸酸甘油三酯(Caprylic/Capric Triglyceride)组成。
14.根据权利要求13所述的用途，其中，所述组合物由10-30％的α-生育酚乙酸酯和70-90％的辛酸/癸酸甘油三酯(Caprylic/Capric Triglyceride)组成。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2015A000139 | 2015-02-03 | ||
| ITMI20150139 | 2015-02-03 | ||
| PCT/EP2016/051215 WO2016124408A1 (en) | 2015-02-03 | 2016-01-21 | Composition for topical application in the auditory canal |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107405302A true CN107405302A (zh) | 2017-11-28 |
| CN107405302B CN107405302B (zh) | 2020-07-31 |
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| CN201680007801.8A Active CN107405302B (zh) | 2015-02-03 | 2016-01-21 | 用于在耳道中局部施用的组合物 |
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| EP (1) | EP3253383B1 (zh) |
| CN (1) | CN107405302B (zh) |
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| AU (1) | AU2016214625B2 (zh) |
| BR (1) | BR112017016652B1 (zh) |
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| DE (1) | DE202015100655U1 (zh) |
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| SI (1) | SI3253383T1 (zh) |
| TR (1) | TR201901911T4 (zh) |
| WO (1) | WO2016124408A1 (zh) |
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| CN109689027A (zh) * | 2016-06-29 | 2019-04-26 | 奥德纳米有限公司 | 甘油三酯耳用制剂及其用途 |
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| IT201900003515A1 (it) * | 2019-03-11 | 2020-09-11 | Gilas Sas Di Carcano Maria Grazia E C | COMPOSIZIONE DERMO-COSMETICA PER USO TOPICO, A BASE DI VITAMINA E e/o SUOI ESTERI |
| IT202000021370A1 (it) * | 2020-09-09 | 2022-03-09 | Sigla S R L | Composizione dermo-cosmetica per uso topico |
| IT202000021367A1 (it) * | 2020-09-09 | 2022-03-09 | Sigla S R L | Composizione a base di vitamina e per uso topico |
| IT202000021373A1 (it) * | 2020-09-09 | 2022-03-09 | Sigla S R L | Composizione dermo-cosmetica per uso topico |
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| CN101053581A (zh) * | 2007-04-30 | 2007-10-17 | 王建林 | 一种治疗中耳炎的外用药物及制备方法 |
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| WO2011085155A2 (en) | 2010-01-07 | 2011-07-14 | Ora, Inc. | Formulations and methods for dissolving cerumen |
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| CN109689027A (zh) * | 2016-06-29 | 2019-04-26 | 奥德纳米有限公司 | 甘油三酯耳用制剂及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| RS58319B1 (sr) | 2019-03-29 |
| AR103607A1 (es) | 2017-05-24 |
| US20180015018A1 (en) | 2018-01-18 |
| PT3253383T (pt) | 2019-01-30 |
| DE202015100655U1 (de) | 2016-02-04 |
| PL3253383T3 (pl) | 2019-05-31 |
| HUE042413T2 (hu) | 2019-06-28 |
| CA2974852C (en) | 2023-05-09 |
| EP3253383A1 (en) | 2017-12-13 |
| EP3253383B1 (en) | 2018-12-26 |
| SI3253383T1 (sl) | 2019-03-29 |
| BR112017016652B1 (pt) | 2023-10-10 |
| DK3253383T3 (en) | 2019-02-18 |
| US10179101B2 (en) | 2019-01-15 |
| MX2017009770A (es) | 2018-03-28 |
| WO2016124408A1 (en) | 2016-08-11 |
| CY1121366T1 (el) | 2020-05-29 |
| AU2016214625B2 (en) | 2020-05-07 |
| BR112017016652A8 (pt) | 2022-07-05 |
| HRP20190328T1 (hr) | 2019-04-19 |
| EA033127B1 (ru) | 2019-08-30 |
| AU2016214625A1 (en) | 2017-08-03 |
| CL2017001889A1 (es) | 2018-04-13 |
| BR112017016652A2 (pt) | 2018-04-10 |
| TR201901911T4 (tr) | 2019-03-21 |
| CN107405302B (zh) | 2020-07-31 |
| CA2974852A1 (en) | 2016-08-11 |
| LT3253383T (lt) | 2019-02-25 |
| ES2711171T3 (es) | 2019-04-30 |
| EA201791332A1 (ru) | 2018-01-31 |
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